For years, biologists have described murine strain differences without determining the underlying causation. The purpose of this research effort is to delineate the reasons for a murine strain difference in cadmium-induced teratogenesis. More specifically, it has been shown that the C57BL/6N strain is susceptible and the SWV/Fnn strain is resistant to the induction of forelimb ectrodactyly (absence of digits) by cadmium administration. It is hypothesized that a proteomics approach to systematically examine differences in protein levels between the two murine strains, both endogenously as well as following cadmium exposure, will be useful for identifying mechanistic pathways for the strain difference. Although this approach will yield tangible differences between the murine strains, it is suggested that by comparatively analyzing the proteomic results together with gene expression profiling and quantitative trait loci (QTL) analysis, two approaches that are being utilized independently to address this same question, the possibility of determining the cause of the strain difference is enhanced. The QTL analysis has preliminarily determined nine chromosomal loci that are linked to the apparently oligogenic trait. If any of the differentially expressed transcripts or proteins can be determined to be from genes that are in the chromosomal regions identified in the QTL analysis, this would significantly enhance both results. It is hypothesized that by examining the cadmium-induced murine strain difference in this malformation via whole genome linkage analysis, gene expression profiling and proteomic analysis, that the individual results will synergize to yield a more significant and comprehensive answer to the question of the causation of the strain difference to cadmium-induced teratogenesis. However, since this same strain difference (C57 more sensitive than SWV) exists for all of the teratogenic agents that have been shown to cause this specific malformation, including some prominent teratogens such as all-trans-retinoic acid, acetazolamide, hyperthermia, and ethanol, it is a goal of this research to determine some fundamental aspects of gene-environment interactions in teratogenesis.